Project Summary/Abstract The progression of Alzheimer?s Disease (AD) appears to initially take place in the hippocampus where memory is formed. Recent studies have demonstrated that impaired neurovascular uncoupling and capillary flow abnormalities precede neurodegeneration and that AD neuropathology is associated with dysregulation of the cerebral circulation and alteration of microvasculature morphology. In vivo imaging of cerebral blood flow (CBF), oxygen saturation (SO2), and cerebral metabolic rate of oxygen (CMRO2) not just in the cortical but also in the subcortical regions is thus of critical importance to study vascular dysfunction during AD progression. Currently available imaging methods are limited either by shallow penetration which only allows imaging superficial cortical layers (eg. optical imaging) or by low spatiotemporal resolution (eg. MRI and CT). The ability to bring together the functional and structural information from a large field-of-view, at a high spatiotemporal resolution would permit new preclinical studies advancing our understanding of the healthy and diseased brain. The goal of this K99/R00 proposal is to develop a novel ultrasound velocimetry and integrate it with photoacoustic oximetry for CBF, SO2, and CMRO2 imaging of the entire rodent brain with ~100 micron-sub second spatiotemporal resolution. Specifically, in Aim 1, the candidate will develop an ultrasound speckle decorrelation- based velocimetry (vUS) for quantitative CBF imaging; in Aim 2, the candidate will implement a multispectral photoacoustic tomography (mPAT) for SO2 and integrate the vUS and mPAT to measure CMRO2. The proposed K99/R00 program will focus on applying the technology to investigate Aim 3: Alzheimer?s disease (AD) in a triple transgenic AD mouse model. The outcome of Aim 3 will improve our understanding of the different time courses of hemodynamics and oxygenation changes, and the cause-and-effect relationship between cerebrovascular alterations and AD neuropathology during the disease progression. The proposed research will be conducted at the BOAS lab/Neurophotonics Center at Boston University, which is an ideal environment for developing biomedical imaging technology and applying it to neuroscience research. A strong mentoring team has been formed by the candidate which includes Dr. David Boas, a pioneer in applying optic imaging for neuroscience study, Dr. Thomas Szabo, an expert in ultrasound technology, Dr. Anna Devor, who has extensive experience in neurovascular coupling and neural imaging, and Dr. Benjamin Wolozin who is an expert in the field of neurodegenerative mechanism and treatment. Through this proposed K99/R00 research and professional development program, the candidate will receive didactic training in AD related neurodegeneration and brain imaging technology development, and also strengthen skills in planning, communication, interviewing, grant writing and laboratory management. By fulfilling the aims, the candidate will be well equipped to become an independent investigator and lead an inter-disciplinary research program.